The PI3K (phosphatidylinositol 3-kinase)-AKT(protein kinase B) pathway is an important signal transduction pathway that plays a central role in cell growth, proliferation, differentiation, invasion, migration, apoptosis, glucose metabolism, or the like. It is known that the PI3K-AKT pathway is constantly activated in plural malignant tumors (Nature Reviews Drug Discovery, Vol. 8, No. 8, pp. 627-644, 2009) by activation of a receptor on the upstream of the PI3K-AKT pathway, or mutation, defect, or amplification of molecules constituting the PI3K-AKT pathway.
It is reported that the PI3K-AKT pathway is involved in not only malignant tumors but also in other diseases, for example, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection (Biochimica et Biophysica Acta Vol. 1784, No. 1, pp. 159-185, 2008).
Therefore, it is considered that regulating the PI3K-AKT pathway is beneficial in a treatment for various diseases.
In addition, the Ras-Raf-MEK (MAP kinase kinase)-ERK (extracellular signal-regulated kinase) pathway is located on the downstream of various receptors, and plays an important role in cell physiological functions, for example, cell proliferation, apoptosis, or cell differentiation (ChemMedChem Vol. 6, No. 1, pp. 38-48, 2011).
Examples of diseases in which the Ras-Raf-MEK-ERK pathway is involved include a malignant tumor, an allergic disease, an autoimmune disease, a neurodegenerative disease, and a circulatory system disease.
Therefore, it is expected that regulating the Ras-Raf-MEK-ERK pathway is beneficial in a treatment for various diseases.
Here, it is reported that the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway complementarily functions regarding cell proliferation, and regulating both the pathways at the same time is beneficial in a treatment for malignant tumors (Cancer Biology & Therapy Vol. 7, No. 2, pp. 307-315, 2008 and Nature medicine, Vol. 14, No. 12, pp. 1351-1356, 2008).
In the treatment of diseases, since the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway are very important, PI3K-AKT pathway inhibitors or Ras-Raf-MEK-ERK pathway inhibitors have been developed thus far. However, the number thereof which became commercially available is very small (Pamphlet of International Publication No. WO2011/064250). In addition, regarding compounds that inhibit both the signal pathways directly and at the same time, there are only a few reports (Japanese National-Phase Publication (JP-A) No. 2009-515854) thus far.
On the other hand, 1,5-naphthyridine derivatives having a urea structure in the molecule that inhibits AurolaB, the Ras-Raf-MEK-ERK pathway, and Erk2 have been known (Pamphlet of International Publication No. WO2011/064250).